Role of peptide transporter PEPT1 in the intestinal absorption and pharmacokinetics of the amino acid ester prodrug valacyclover

摘要: Purpose. The study evaluated the quantitative contribution of PEPT1 to intestinal permeability valacyclovir, an ester prodrug antiviral drug acyclovir. Methods. Valacyclovir effective (Peff) was examined by in situ single-pass perfusion studies performed wildtype and Pept1 knockout mice. In particular, valacyclovir Peff measured as a function perfusate pH, potential inhibitors, concentrations segments under steady-state conditions. calculated as: = -Q×ln(Cout/Cin)/(2πRL), after correcting for water flux with gravimetric method well luminal degradation. At end procedures, portal vein plasma samples were collected analyzed determine extent bioconversion valacyclovir. All using validated HPLC coupled fluorescence detection. Results. jejunal mice significantly inhibited glycylsarcosine cefadroxil, suggesting PEPT1-specific active uptake kinetics jejunum fitted major Michaelis– 39 Menten term (apparent affinity constant Km=10 mM) minor linear term. values comparably high duodenum, ileum substantial lower colon mice, finding consistent not being expressed large intestine. small reduced about 90% compared that different from Peff. No significant differences observed between two genotypes. Jejunal also insensitive changes pH over range 5.5 7.5. samples, only acyclovir detected while levels below limit Conclusions. Our findings demonstrate accounted approximately mouse Other membrane transporters appeared play role, if any, facilitating absorption rapidly completely converted acyclovir, current conditions, passing wall.